IRREVERSIBLE DIMERIZATION TETRAMERIZATION AND POSTTRANSLATIONAL MODIFICATIONS INHIBIT PROTEOLYTIC DEGRADATION OF A-BETA-PEPTIDES OF ALZHEIMERS-DISEASE/

Experimental evidence increasingly implicates the beta-amyloid peptide in the pathogenesis of Alzheimer's disease. beta-amyloid filaments dr amatically accumulate in the neuritic plaques and vascular deposits as the result of the brain's inability to clear these structures. In thi s paper, we demonstrate that in addition to the intrinsic stability of A beta N-42, the time dependent generation of irreversibly associated AP dimers and tetramers incorporated into A beta filaments are themse lves resistant to proteolytic degradation. The presence of post-transl ational modifications such as isomerization of aspartyls 1 and 7, cycl ization of glutamyl 3 to pyroglutamyl and oxidation of methionyl 35, f urther contribute to the insolubility and stability of A beta. All the se factors promote the accumulation of neurotoxic amyloid in the brain s of patients with Alzheimer's disease, and should be considered in th erapeutic strategies directed towards the dissociation of the brain's A beta filaments. (C) 1998 Elsevier Science B.V. All rights reserved.